What is the role of hepcidin deficiency in the pathogenesis of hemochromatosis?

Updated: Apr 03, 2017
  • Author: Andrea Duchini, MD; Chief Editor: Praveen K Roy, MD, AGAF  more...
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Answer

All types of hemochromatosis have been found to originate from the same metabolic error: disruption of tendency for circulatory iron constancy. Severe iron overload was found in patients with mutations of genes encoding hemojuvelin. These changes correlated with a low level of hepcidin. [21] Hepcidin is a human antimicrobial peptide synthesized in the liver [22] that plays a key role in the downregulation of iron release by enterocytes and macrophages (inhibits iron absorption in the gut and iron mobilization from the hepatic stores). The degradation of cellular iron exporter (ferroportin) caused by hepcidin is the mechanism of cellular iron efflux inhibition. The absence of this peptide is associated with severe, early-onset, iron-loading phenotype. It is also inappropriately low in adult-onset HFE -related disease. [23]

Hepcidin synthesis remains under the regulatory influence of hemojuvelin, which is a member of the repulsive guidance molecule (RGM) and is the coreceptor of the bone morphogenetic protein (BMP). De-arranged BMP signaling in hemojuvelin mutants associated with hemochromatosis disturbs hepcidin synthesis in hepatocytes. Thus, decreased BMP signaling by hemojuvelin disfunction lowers hepcidin secretion. The hepcidin deficiency due to mutations of hepcidin gene or genes of hepcidin regulators is supposed to be the main factor leading to different types of hemochromatosis.


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